Craniofacial abnornialities involving the first branchial arch derivatives, including jaw,,palate, and teeth, are a major class of birth defects in humans. Understanding the molecular genetic mechanisms behind craniofacial development is vital to devising innovative methods for diagnosis, prevention, and treatment of human defects. The long-term goal of niy research is to characterize the transcriptional network that governs development of the first branchial arch, by identifying transcription factors and cis-regulatory elements important in this process, and determining th^eir hierarchic^ relationship. Lhx6 and Lhx3 genes, encoding homeodomain transcription factors, are major regulators of first branchial arch development; mouse mutants lacking the activities of both Lhx6 and Lhx8 are born with cleft secondary palate and no molars. Specifically, I found that the Lhx genes are essential for the initial steps of molar and secondary palate development. Two crucial questions remain on the function and regulation of Lhx genes in craniofacial development: 1) what is the molecular and cellular mechanisms of Lhx function during the initiation of tooth and palate development?, and 2) what are the upstream factprs that regulate the expression of the Lhx genes in the first branchial arch? My research during'ROO phase will address these questions using mouse mutant models as well as biochemistry and molecular biology methods. The results of this project will provide critical information on how disruption in Lhx6 and Lhx8 function and expression can contribute to human craniofacial defects.